Download Sleep-Disordered Breathing and Cardiovascular

Sleep-Disordered Breathing and Cardiovascular Disorders
Rohit Budhiraja MD, Pooja Budhiraja MD, and Stuart F Quan MD
Introduction
Obstructive Sleep Apnea and Hypertension
Obstructive Sleep Apnea and Coronary Artery Disease
Sleep-Disordered Breathing and Congestive Heart Failure
Sleep-Disordered Breathing and Arrhythmias
Sleep-Disordered Breathing and Stroke
Potential Pathogenetic Mechanisms of Cardiovascular Disease in
Sleep-Disordered Breathing
Sleep-Disordered Breathing and Excess Mortality
Summary
Compelling data demonstrate a strong association between sleep-disordered breathing (SDB) and
cardiovascular disorders. The association is most consistent between obstructive sleep apnea (OSA)
and hypertension. Epidemiologic and clinic-based studies provide evidence for an etiological role of
OSA in hypertension, independent of obesity. Furthermore, several studies suggest amelioration of
hypertension with therapy for sleep apnea. Emerging data also suggest a role for OSA in causing
coronary artery disease. This association is bolstered by evidence suggesting that continuous positive airway pressure (CPAP) therapy improves early signs of atherosclerosis and may impede
progression to clinically important cardiovascular disease. SDB (both OSA and central sleep apnea)
is frequently observed in patients with heart failure. OSA may be a risk factor for incident heart
failure. The current data do not provide consistent evidence for whether treatment of SDB will
improve survival or other end points in patients with heart failure, and larger trials are currently
underway to better elucidate that relationship. Substantial evidence also links SDB to an increased
risk of various arrhythmias. Treatment of SDB with CPAP appears to significantly attenuate that
risk. Finally, several studies suggest SDB as a risk factor for stroke. Whether treatment of SDB
reduces stroke risk, however, remains to be determined. In conclusion, persuasive data provide
evidence for an association, probably causal, between sleep-disordered breathing and several cardiovascular disorders. Large randomized controlled trials will further help confirm the association
and elucidate the cardiovascular benefits of SDB therapy. Key words: sleep-disordered breathing;
cardiovascular disease; obstructive sleep apnea; OSA; hypertension; obesity; continuous positive airway
pressure; CPAP; atherosclerosis. [Respir Care 2010;55(10):1322–1330. © 2010 Daedalus Enterprises]
Rohit Budhiraja MD and Pooja Budhiraja MD are affiliated with the
Department of Medicine, Southern Arizona Veterans Affairs Health Care
System, and with the Department of Medicine, University of Arizona
College of Medicine, Tucson, Arizona. Rohit Budhiraja MD is also affiliated with the Arizona Respiratory Center, University of Arizona College of Medicine, Tucson, Arizona. Stuart F Quan MD is affiliated with
the Arizona Respiratory Center, University of Arizona College of Medicine, Tucson, Arizona, and with the Division of Sleep Medicine, Harvard Medical School, and Brigham and Women’s Hospital, Boston Massachusetts.
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Dr Quan presented a version of this paper at the 45th RESPIRATORY CARE
Journal Conference, “Sleep Disorders: Diagnosis and Treatment,” held
December 10-12, 2009, in San Antonio, Texas.
This research was partly supported by National Institutes of Health grant
HL53938 and Stanford University subcontract HL068060.
Correspondence: Stuart F Quan MD, Division of Sleep Medicine, Harvard Medical School and Brigham and Women’s Hospital, 401 Park
Drive, 2nd Floor East, Boston MA 02215. E-mail: [email protected].
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Introduction
Sleep-disordered breathing (SDB), expressed most frequently as obstructive sleep apnea (OSA), is a common
syndrome, and becomes progressively more prevalent with
increasing age.1 For the past several decades, a number of
cross-sectional studies, performed primarily in relatively
small clinical cohorts or using surrogates such as snoring
as markers of SDB, have reported linkages between SDB
and cardiovascular disease. For example, a high prevalence of OSA has been observed in patients with hypertension.2 Conversely, hypertension is found in a large percentage of OSA patients. With respect to cardiac disease,
early studies linked OSA to ischemic heart disease.3,4 In
addition, it has been shown that OSA is associated with
deterioration in left-ventricular function5 and that treatment of OSA with continuous positive airway pressure
(CPAP) improves cardiac function. If SDB plays a causal
role in the pathogenesis of cardiovascular disease, higher
mortality would be expected among individuals with OSA.
This hypothesis was supported in some6,7 but not all8 retrospective studies. Whether SDB is an independent risk
factor for cardiovascular disease is an important public
health question. According to the 1999 –2000 National
Health and Nutrition Examination Survey, the prevalence
of hypertension in the United States in those over age
55 years is 48%.9 According to the year 2000 census, there
are approximately 59 million Americans age 55 or older.
If 25–50% of these individuals also have OSA, then 14 –29
million of those people are at increased risk for cardiovascular disease or excess mortality related to OSA.
In the past several years a persuasive body of data now
indicates a causal association, independent of obesity, between SDB and cardiovascular disorders such as hypertension, coronary artery disease, arrhythmias, congestive
heart failure, and stroke. The association is strongest and
most consistent between OSA and hypertension. This review will summarize the most important studies demonstrating the linkages between SDB and cardiovascular disease, and outline potential responsible mechanisms.
Obstructive Sleep Apnea and Hypertension
Cogent data confirm the association between OSA and
hypertension.10 Several epidemiologic and clinic-based
studies conducted in cross-sectional as well as longitudinal
designs have demonstrated a strong and consistent relationship between these disorders. Peppard et al found a
causal association between SDB at baseline and the presence of hypertension 4 years later in 709 subjects in the
Wisconsin Sleep Cohort, and the odds of hypertension
increased with increasing baseline AHI.11 The association
was independent of age, sex, body mass index, waist and
neck circumference, baseline hypertension, smoking, and
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alcohol use. The odds ratios for hypertension continued to
be significant when those hypertensive at baseline were
excluded. Recent analyses of data from this cohort demonstrated dose-response increased odds of incident nocturnal non-dipping of systolic blood pressure, a risk factor for
hypertensive complications, in participants with SDB over
an average of 7.2 years of follow-up.12
A cross-sectional analysis of the Sleep Heart Health
Study arrived at similar conclusions.13 Persons with an
AHI ⱖ 30 events/h had a 1.37-fold greater odds of hypertension than those without OSA (AHI ⬍ 1.5 events/h),
after adjusting for several confounders. However, recent
prospective analyses of data from the Sleep Heart Health
Study found that the relationship between the baseline
AHI and the risk of developing hypertension approached
but did not quite reach statistical significance after adjustment for body mass index.14 However, the odds ratio in the
longitudinal analysis was quite similar to that in the crosssectional analysis, suggesting that a causal relationship is
most likely present and obscured by residual confounding.
The older age of participants in this study, exclusion of
those with baseline hypertension, and different methods of
diagnostic testing are among the potential reasons the results of these analyses differ from those of the Wisconsin
Sleep Cohort.15-17
Other epidemiologic and clinic-based studies provide
corroborating evidence for an association between SDB
and hypertension. In the Nurses Health Study, snoring, a
surrogate symptom of SDB, was associated with an increased risk of incident hypertension over an 8-year follow-up period.18 The Outcomes of Sleep Disorders in Older
Men Study (an ancillary study of the Osteoporotic Fractures in Men Study) revealed 1.6-fold higher odds of hypertension in elderly men with SDB.19 Persons with OSA
also have a significantly higher prevalence of non-dipping
of blood pressure at night.20 Conversely, drug-resistant or
poorly controlled hypertension is associated with a high
prevalence of concomitant undiagnosed SDB.21,22
Another line of evidence supporting SDB as a causal
factor in hypertension is provided by trials demonstrating
amelioration, albeit modest, of hypertension with therapy
of sleep apnea.23 The changes in mean blood pressure after
CPAP have been suggested to be on the order of
2–5 mm Hg.24 Studies cumulatively suggest better antihypertensive response with CPAP in patients with daytime
sleepiness than those without excessive sleepiness.25-27 Refractory hypertension may also improve with CPAP therapy in persons with comorbid OSA.21 In addition, mandibular advancement devices and otolaryngological surgery
are associated with improvement in blood pressure in patients with OSA.28
However, there has been a lack of consistent demonstration of antihypertensive effects of OSA therapy.29 This
discrepancy may emanate from diverse populations and
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sample sizes, varying diagnostic techniques, and different
definitions for apneas and hypopneas, as well as dissimilar
follow-up periods in different studies.
In conclusion, consistent data suggest a strong causal
association between OSA and hypertension. Preliminary
trials evaluating therapy of OSA suggest amelioration of
hypertension in some subgroups with sleep apnea, but larger
prospective trials are clearly needed to unambiguously elucidate the effects of OSA therapy on blood pressure and
related outcomes.
Obstructive Sleep Apnea
and Coronary Artery Disease
The evidence suggesting an association between OSA
and coronary artery disease continues to accrue. One study
showed an increased prevalence and extent of coronary
artery calcium, a marker of subclinical coronary artery
disease, in patients with OSA.30 Presence of sleep apnea in
the Osteoporotic Fractures in Men Study cohort was associated with 1.2-fold increased odds of the presence of
cardiovascular disease.19 Cross-sectional analyses of data
from the Sleep Heart Health Study revealed higher odds of
self-reported coronary artery disease, heart failure, and
stroke in persons with high AHI.31 Preliminary longitudinal analyses of the Sleep Heart Health Study data indicate
that the risk of incident coronary artery disease is primarily in men less than age 70 years.32
Other prospective observational studies in clinical populations have demonstrated a higher incidence of cardiovascular disorders in persons with OSA33,34 as well. Cardiovascular mortality is also increased in OSA.35 One study
with a mean of 10.1 years of follow-up found that participants with untreated severe OSA had a higher incidence
of fatal cardiovascular and non-fatal cardiovascular events,
compared to healthy participants.36 However, this latter
study was recruited from a clinical population and included only men.
In persons with coronary artery disease undergoing elective percutaneous intervention, OSA is associated with
restenosis and vessel remodeling.37 There is also an increase in the incidence of major adverse cardiac events
such as revascularizations and cardiac mortality after percutaneous intervention in patients with OSA.38 Furthermore, OSA patients demonstrate smaller increases in leftventricular ejection fraction and regional wall motion within
the infarct area days after percutaneous intervention.39 Finally, treatment of OSA after percutaneous intervention is
associated with a reduction in the number of cardiac
deaths.40
Treatment of OSA may alleviate cardiovascular risk.
One study revealed significantly lower combined end points
of cardiovascular death, acute coronary syndrome, hospitalization for heart failure, or need for coronary revascu-
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larization in persons treated for OSA, compared to those
with OSA who declined therapy (hazard ratio 0.24).41 In
the study by Marin et al,36 cardiovascular disease risk in
those with severe OSA treated with CPAP was the same as
in non-OSA patients.
As outlined in the foregoing discussion, accumulating
data in cross-sectional and longitudinal observational studies implicate SDB as an independent risk factor for cardiovascular disease. In addition, evidence suggests that
CPAP therapy improves early signs of atherosclerosis and
may impede progression to clinically important cardiovascular disease.42 Cardiac biomarkers such as C-reactive protein may decline with CPAP treatment as well.43 Nevertheless, there have been no large-scale randomized studies
demonstrating that treatment of SDB reduces cardiovascular disease risk. Recently, however, 2 large randomized
clinical trials were started to determine whether OSA treatment impacts cardiovascular disease risk. In Europe, a
large prospective randomized CPAP intervention in 400
patients with coronary artery disease and OSA is aimed at
assessing the impact of CPAP treatment on a composite
end point of new revascularization, myocardial infarction,
stroke, and cardiovascular mortality over a 3-year period
in persons with coronary artery disease and OSA.44 In the
United States, the multicenter HeartBEAT study will randomize 352 subjects with OSA and coronary artery disease or coronary artery disease risk factors to CPAP, lowflow nocturnal oxygen, and health-lifestyle instruction to
determine whether CPAP or oxygen affects cardiac biomarkers. Another clinical trial, the Continuous Positive
Airway Pressure Treatment of Obstructive Sleep Apnea to
Prevent Cardiovascular Disease, is being conducted in several international sites to determine whether CPAP will
reduce incident cardiovascular disease. Enrollment of 5,000
subjects is planned, with study sites in Australia, China,
India and New Zealand.
In conclusion, data suggesting an association between
OSA and clinical and subclinical coronary artery disease
continue to accrue. Large prospective trials will help better
elucidate the impact of OSA therapy on improvement of
cardiovascular morbidity.
Sleep-Disordered Breathing
and Congestive Heart Failure
SDB is present in approximately three fourths of patients with symptomatic or decompensated systolic heart
failure.45,46 The prevalence is very high, even in those with
stable chronic heart failure.47-49 Cross-sectional analyses
from the Sleep Heart Health Study data revealed an adjusted odds ratio of 2.2 for self-reported heart failure among
subjects with OSA.31 Of all heart-failure patients with sleep
apnea in one study, 40% had AHI ⬎ 30 events/h.47 Patients with SDB were older and had higher body mass
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index and brain-natriuretic peptide, despite similar leftventricular ejection fraction and functional class of heart
failure. There is little published longitudinal data, but preliminary longitudinal analyses of data from the Sleep Heart
Health Study indicate that men, but not women, have an
increased risk of incident congestive heart failure as a
consequence of SDB, even after exclusion of subjects with
central sleep apnea.32
Both OSA and central sleep apnea are encountered in
heart-failure patients, and the proportion of these events
has differed in different studies. It has been suggested that
the reduction in PaCO2 and increase in lung-chemoreceptor
circulation time in such patients can result in an overnight
shift in the predominant apnea type from obstructive to
central. Central sleep apnea is frequently accompanied by
Cheyne-Stokes respiration, a breathing pattern characterized by repetitive sinusoidal waxing and waning of tidal
volume amplitude.
Central sleep apnea is an independent predictor of mortality in patients with heart failure or cardiac transplantation.50,51 The hazard ratio for early mortality in heart-failure patients with central sleep apnea in one study was 2.1
relative to those without central sleep apnea.50 CheyneStokes respiration is also associated with higher mortality.52 Furthermore, central sleep apnea/Cheyne-Stokes respiration may also promote cardiac electrical instability,
with impaired heart-rate variability and enhanced occurrence of cardiac arrhythmias.53
Obstructive events are associated with a marked negative swing in intrathoracic pressure, which can lead to
increased pre-load and after-load. Furthermore, sympathetic activation resulting from SDB and arousals can
deteriorate cardiac function. CPAP therapy improves leftventricular ejection fraction and quality of life in heartfailure patients with OSA.54,55 CPAP use also decreases
myocardial irritability and risk of arrhythmias.56
The prevalence of SDB is high not only in systolic heart
failure but also in heart failure with normal ejection fraction. One study of 247 patients with heart failure with
normal ejection fraction found SDB in 69%, OSA in 40%,
and central sleep apnea in 29%.57 Central sleep apnea was
associated with higher pulmonary artery wedge pressure
and brain-natriuretic peptide, and lower PaCO2. Persons with
central sleep apnea had a larger left atrial diameter than
those with OSA, who in turn had more pronounced atrial
enlargement than those with no SDB. However, whether
diastolic dysfunction leads to SDB or vice versa is yet to
be clearly elucidated. Presence of left-ventricular hypertrophy in OSA and regression of hypertrophy with CPAP
has been documented in smaller studies.58,59
The effect of PAP therapy on central sleep apnea in
patients with heart failure is not clearly understood. The
Canadian Continuous Positive Airway Pressure Trial for
Congestive Heart Failure Patients With Central Sleep Ap-
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nea (CanPAP) trial was designed to answer this question.60
CPAP improved nocturnal oxygenation, cardiac ejection
fraction, and 6-minute walk distance, and lowered norepinephrine level, but did not improve heart-transplant-free
survival or significantly alleviate central sleep apnea in
many of the trial participants. Post-hoc analyses revealed
significantly better transplant-free survival (hazard ratio
0.371, P ⫽ .043) in subjects whose AHI had been reduced
to less than 15 events/h, compared to control subjects.
Whether advanced methods of applying PAP in heart-failure patients will be more efficacious is unknown. Small
clinical studies suggest that both bi-level PAP and adaptive servo ventilation may benefit some patients with central sleep apnea and heart failure.61 Larger trials are underway.
Some studies have evaluated the effect of cardiac pacing on SDB. While one study suggested that atrial overdrive pacing can improve SDB,62 other studies have failed
to consistently confirm this effect.63,64 It appears that pacing may have some benefits in alleviating SDB in patients
with heart failure with predominantly central sleep apnea.65 However, larger trials are required to clearly understand the magnitude and physiologic basis of this effect.
The effect of cardiac resynchronization therapy on central
sleep apnea/Cheyne-Stokes respiration in patients with
chronic heart failure has been more consistently demonstrated.66,67 An improvement in cardiac output and decreased pulmonary vascular congestion may be responsible for improvement of central events in heart failure.
In summary, SDB in the form of both OSA and central
sleep apnea is frequently observed in patients with heart
failure. Improvement in cardiac function with cardiac resynchronization therapy may improve central sleep apnea.
OSA may be a risk factor for incident heart failure, but it
is currently unclear whether treatment of either OSA or
central sleep apnea, or both forms of SDB will reduce the
incidence of heart failure or improve survival in patients
with heart failure.
Sleep-Disordered Breathing and Arrhythmias
Diverse cardiac arrhythmias such as atrial fibrillation,
nonsustained ventricular tachycardia, and complex ventricular ectopy have been described in persons with SDB.68
It has been suggested that atrial fibrillation has a strong
association with central sleep apnea, whereas complex ventricular ectopy is more closely associated with OSA.69
Conversely, the prevalence of undiagnosed OSA in patients with cardiac pacemaker implantation for diverse reasons is extremely high.70 Several mechanisms such as hypoxia, sympathetic activation and swings in intrathoracic
pressure may explain this association. Recent analyses from
the Sleep Heart Health Study demonstrated a 17-fold increased odds of an arrhythmia (atrial fibrillation and non-
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sustained ventricular tachycardia) occurring after a respiratory disturbance than an arrhythmia occurring after
normal breathing during sleep,71 providing corroborating
evidence for the link between SDB events and arrhythmias. Arrhythmias can be severe and potentially lifethreatening. One study of 112 persons who had undergone
polysomnography and had died suddenly from cardiac
cause suggested that the peak in sudden cardiac death in
those with OSA occurs primarily from midnight to 6 AM
(ie, during the sleeping hours) (relative risk 2.6).72
The risk of arrhythmias in OSA significantly decreases
with CPAP therapy. In an elegant study, arrhythmias were
evaluated in 23 patients with moderate to severe OSA over
a 14-month period, using a subcutaneously implanted loop
recorder. The follow-up duration included 2 months with
no OSA therapy, and 12 months thereafter on CPAP. The
occurrence of severe arrhythmias was common prior to
CPAP therapy, but decreased rapidly after initiation of
CPAP therapy, with no ectopy recorded during the last
6 months of follow-up. Another study demonstrated lower
recurrence of atrial fibrillation after elective cardioversion
in OSA patients who were treated with CPAP therapy.73
In summary, substantial evidence links SDB as an etiologic factor in the pathogenesis of various arrhythmias,
particularly atrial fibrillation. Treatment of SDB with CPAP
appears to reduce this risk.
Sleep-Disordered Breathing and Stroke
Several studies suggest that SDB is a risk factor for
stroke.74 However, these studies have been primarily case
series, case-control studies, or used snoring as a surrogate
for objective documentation of SDB. More recently, an
observational cohort study in a clinical population found
an increased rate of the composite outcome of stroke or
death in patients with OSA over a 4-year interval, in comparison to those without OSA, with an adjusted hazard
ratio of 1.97.75 Similar findings have been observed in the
Wisconsin Cohort Study over a 4-year interval, although
the fully adjusted odds ratio failed to reach statistical significance, in part because of inadequate study power.76
More recently, analysis of prospective data from the Sleep
Heart Health Study suggested that severe SDB is an independent risk factor for stroke only in men.77 Whether treatment of SDB reduces stroke risk remains to be determined.
Although there are now substantial data indicating that
SDB is a risk factor for stroke, the converse also is true in
that stroke appears to be a risk factor for the development
of SDB.74 Unfortunately, CPAP is not well tolerated in
post-stroke patients, and long-term adherence to CPAP
therapy is low. Nevertheless, it appears that long-term survival after stroke is better among patients who adhere to
CPAP therapy.78
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To summarize, SDB appears to be a risk factor for
stroke, and, conversely, stroke is a risk factor for SDB.
However, it is unclear whether treatment of SDB reduces
long-term stroke risk. SDB also is a risk factor for subsequent cardiovascular disease events after stroke. CPAP
treatment of SDB after stroke may reduce that risk, but
long-term adherence is difficult to achieve.
Potential Pathogenetic Mechanisms
of Cardiovascular Disease
in Sleep-Disordered Breathing
Several SDB-related mechanisms, including endothelial
dysfunction, hypoxia, inflammation, obesity, metabolic
dysregulation, and sympathetic activation, may influence
the pathogenesis of cardiovascular disease in persons with
SDB. OSA is associated with intermittent hypoxemia, consequent to intermittent upper-airway occlusion. Hypoxia
and attendant hypercapnia augment sympathetic nervous
system activity. Recurrent hypoxemia-re-oxygenation produces sustained hypertension in rodents, via sympathetic
activation.79 The intrathoracic pressure swings and arousals associated with hypopneic and apneic events also boost
sympathetic activity
Intermittent hypoxemia may also be pivotal in the genesis of systemic inflammation in OSA. Intermittent hypoxemia increases the expression of transcription factors such
as activator protein 1 and nuclear factor kappa 〉, which
then up-regulates expression of inflammatory cytokines
and adhesion molecules.80 Indeed, the circulating levels of
C-reactive protein,81,82 soluble interleukin-6 receptors,83
intracellular adhesion molecule-1, and vascular-cell adhesion molecule-1 are elevated in persons with OSA.84,85
Furthermore, the propensity of monocytes to adhere to
vascular endothelium is increased.86 Increased levels and
adherence of inflammatory mediators contribute to atherosclerosis.87 Production, migration, and adherence of these
mediators is favorably modified by OSA treatment.86,88
Additionally, hypoxia re-oxygenation, sympathetic activation, and increased lipid peroxidation amplify freeradical production.89 There is enhanced free-radical production from neutrophils and monocytes in OSA, and this
ameliorates with therapy.86,90,91 Oxidant stress contributes
to endothelial injury, increased production of adhesion molecules in the endothelium, diminished vasodilator production, and atherosclerosis.92
The hypoxia-regeneration, inflammation, and oxidative
stress contribute to endothelial injury and, thence, vasoconstriction, hypercoagulability, and atherosclerosis.86
These pathways may constitute the mechanistic paradigm
whereby OSA mediates the genesis or worsening of hypertension and other cardiovascular disorders (Fig. 1).
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verse cardiovascular disorders, as well as increased mortality. Large, prospective, long-term studies will help further confirm this relationship. The current data also suggest
a beneficial role of CPAP therapy in attenuating the risk of
adverse cardiovascular sequelae. However, conclusive evidence of the salutary role of SDB therapy will require
large randomized controlled studies designed with careful
attention to the potential confounders, as well as aimed at
elucidating the mechanistic pathways whereby SDB therapy provides cardiovascular benefits.
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Fig. 1. Pathogenetic mechanisms whereby sleep-disordered
breathing leads to cardiovascular sequelae. (Adapted from Reference 92.)
Sleep-Disordered Breathing and Excess Mortality
As previously discussed, most retrospective studies indicate that OSA is a risk factor for decreased long-term
survival. More recently, 3 observational cohort studies confirmed that SDB appears to increase mortality. In an 18year follow-up of the Wisconsin Sleep Cohort, the adjusted hazard ratio for all-cause mortality with severe SDB
versus no SDB was 3.0, and the cardiovascular-diseasespecific hazard ratio was 5.2.93 Similarly, a 14-year follow-up of the Busselton Health Study found the fully adjusted hazard ratio for all-cause mortality associated with
moderate to severe OSA was 6.24.94 However, in both
studies the confidence intervals were wide and the precision of the estimate is uncertain. More recently, with an
average follow-up duration of 8.2 years, the Sleep Heart
Health Study found a fully adjusted hazard ratio for allcause mortality of 1.46, with much narrower confidence
intervals. In addition, death in men accounted for most of
the effect. Coronary-heart-disease-specific mortality
showed the same pattern, and it appeared that nocturnal
hypoxemia was an important mediating factor.95 Although
treatment of OSA with CPAP reduced the risk of fatal and
non-fatal cardiovascular events in a clinically derived observational cohort composed of only men,36 a randomized
controlled trial has not been performed, so it remains to be
definitively determined whether treatment of SDB reduces
all-cause mortality.
Summary
There is compelling evidence suggesting an association,
probably causal, between SDB, especially OSA, and di-
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Discussion
Kapur: Stuart, a lot of people accept the fact that OSA is a cause of
hypertension, but when we’re talking
about coronary disease, congestive
heart failure, or stroke, where do you
think we are on the continuum to proving causation. If we’re not there yet,
what needs to be done to able to make
that statement about these other relationships?
Quan: I think it would be good to
have more data on women and various other segments of the population.
In hypertension there are a lot of (albeit small) clinical studies where they
used CPAP and found a decrease in
blood pressure or they used less drug.
In coronary heart disease we don’t
have good data to show that CPAP
does a lot. There is the Marin study1
and the Yaggi study,2 but neither were
randomized controlled studies. I don’t
like the Yaggi study because they used
a combined outcome variable of stroke
or death, and I think that’s very messy.
So was it stroke or death?
Anyway, I think that we need interventional studies to demonstrate
that doing something is important. We
also need to determine if some segments of the population are more susceptible to the adverse cardiovascular
impact of sleep apnea.
1. Marin JM, Carrizo SJ, Vincente E, Agusti
AG. Long-term cardiovascular outcomes in
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CARDIOVASCULAR DISORDERS
92.
93.
94.
95.
issues for assessment in the different vascular beds: a statement by
the Working Group on Endothelin and Endothelial Factors of the
European Society of Hypertension. J Hypertens 2005;23(1):7-17.
Budhiraja R, Parthasarathy S, Quan SF. Endothelial dysfunction in
obstructive sleep apnea. J Clin Sleep Med 2007;3(4):409-415.
Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ,
et al. Sleep-disordered breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort. Sleep 2008;31(8):1071-1078.
Marshall NS, Wong KK, Liu PY, Cullen SR, Knuiman MW, Grunstein RR. Sleep apnea as an independent risk factor for all-cause
mortality: the Busselton Health Study. Sleep 2008;31(8):1079-1085.
Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB,
O’Connor GT, et al. Sleep-disordered breathing and mortality: a
prospective cohort study. PLoS Med 2009;6(8):e1000132.
men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464):
1046-1053.
2. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke
and death. N Engl J Med 2005;353(19):
2034-2041.
Owens: In the study you showed
with the C-reactive protein data,1 it
seemed that the patients who were nonadherent had a lower C-reactive protein level at the start of the trial, but at
the end of the trial their C-reactive
protein was about the same as those
who had been adherent to treatment.
Is C-reactive protein a marker of symptoms from the disease? And can we
use it to predict who might symptomatically benefit from treatment and
therefore will probably be adherent to
therapy? Or can we use biomarkers to
predict who needs to be treated?
1. Steiropoulos P, Tsara V, Nena E, Fitili C,
Kataropoulou M, Froudarakis M, et al. Effect of continuous positive airway pressure
treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007;
132(3):843-851.
Quan: That’s why we’re doing the
HeartBEAT study.1 About the Chest
article,2 as a clinician reading that sort
of paper you say, “Oh yeah, they had
a large number of people,” but to an
epidemiologist that’s puny. Those differences in C-reactive protein between
people who refused and people who
got treated weren’t significant, but if
they studied 1,000 people, they have
might been significant. It’s hard to
know.
1. Redline S. Phase II trial of sleep apnea treatment to reduce cardiovascular morbidity.
http://projectreporter.nih.gov/project_info
_description.cfm?aid⫽7853407. Accessed
June 24, 2010.
2. Steiropoulos P, Tsara V, Nena E, Fitili C,
Kataropoulou M, Froudarakis M, et al. Effect of continuous positive airway pressure
treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007;
132(3):843-851.
Malhotra: It’s easy for those of us
who were not on the scene in the mid1990s to criticize. Some say that we
should have designed the Sleep Heart
Health Study differently so that there
wasn’t a survivor cohort; they were
older, asymptomatic, and there wasn’t
a lot of disease there. Wasn’t the primary outcome all-cause mortality in
all comers?
Quan: That was one of them. We
had a number of what we called primary hypotheses. One was all causes
of mortality, and another was cardiovascular disease, among others.
Malhotra: My understanding is that
the age over 70 or under 70 was not
pre-specified and that was sort of just
based on results. Is that right? And gen-
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der stratification was a secondary outcome?
Quan: That was brought up by one
of the reviewers for PLoS [Public Library of Science] Medicine, in looking at whether age of death was a prespecified outcome variable.
Malhotra: But the 70 cut-off
wasn’t?
Quan: No, but we had to put a cutoff somewhere. We had tried a few
other cut-off points and it didn’t matter too much.
Malhotra: If you had to redesign that
study, what would you do differently?
Quan: Basically recruit an entire
new cohort.
Malhotra: Not a survivor cohort?
Quan: Not a survivor cohort, but the
cohort we used was recruited for financial reasons. The National Institutes of
Health wanted to do an observational
cohort study. The Sleep Heart Health
Study,1 all told, in direct costs was probably $20 million. Observational cohort
studies are very expensive, and so they
felt that they could reduce the costs by
strapping a study onto other studies.
They basically came up with the design
that’s been used subsequently by several other cohort studies.
1. Quan SF, Howard BV, Iber C, Kiley JP,
Nieto FJ, O’Connor GT, et al. The Sleep
Heart Health Study: design, rationale, and
methods. Sleep 1997;20(12):1077-1085.
Malhotra: Would it have been
cheaper if you didn’t have to go
8 years? For example, if you had a
bigger sample with more events, could
you have after 4 years—which was
the original design?
Quan: It’s possible, but I think that
although the Wisconsin cohort was
much smaller,1 their mortality data are
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CARDIOVASCULAR DISORDERS
out a long time too. Terry Young’s
confidence intervals in the mortality
study were very wide,2 which means
that the precision was very low.
1. Young T, Palta M, Dempsey J, Peppard
PE, Nieto FJ, Hla KM. Burden of sleep
apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study.
WMJ 2009;108(5):246-249.
2. Young T, Finn L, Peppard PE, Szklo-Coxe
M, Austin D, Nieto FJ, et al. Sleep-disordered breathing and mortality: eighteenyear follow-up of the Wisconsin sleep cohort. Sleep 2008;31(8):1071-1078.
Malhotra: Terry Young’s study was
in a community cohort as well, right?
I’m wondering if you wouldn’t have
had a more symptomatic, more affected group and a bigger sample and
not needed 18 years of follow-up? I
don’t know.
Quan: That’s possible. If I were to
design this again and money was no
object, I would recruit a huge cohort,
more along the size of the Women’s
Health Initiative.1 And it would include people who were nonsymptomatic. Obviously, by having
such a huge cohort you would have
symptomatic and non-symptomatic individuals. You would answer the question, which symptoms are important?
You’d have a wide spectrum. I say we
need to do a birth cohort study like the
National Children’s Study. 2 That
would be ideal. We then could wait
for about 40 years for some answers.
1. Women’s Health Initiative Study Group.
Design of the women’s health initiative clinical trial and observational study. Control
Clin Trials 1998;19:61-109.
2. The National Children’s Study. http://www.
nationalchildrensstudy.gov/about/
overview/pages/default.aspx. Accessed
June 24, 2010.
Malhotra: I talked to the Nurses’
Health Study (http://www.channing.
harvard.edu/nhs) people. They prospectively followed 100,000 women.
You can’t do it for less than $100 million unless you have some kind of substandard diagnostic technique.
RESPIRATORY CARE • OCTOBER 2010 VOL 55 NO 10
Quan: It is very hard to do these studies inexpensively. You could cut down
by doing a limited sleep study. However, the spinoff on these cohort studies is that the Sleep Heart Health Study
has published more than 50 papers,
many of which don’t relate to the primary hypothesis at all, because we accumulated all this information. If we
had not done EEG [electroencephalography], we would not have had
those data on arousals, for example.
Kapur: Stuart, given the data you
presented on higher cardiovascular
risk and higher potential cardiovascular mortality in an observational cohort, particularly in men and those who
have more severe apnea, are there ethical limits on what kind of randomized clinical trials we can do? This is
the sort of issue that people who design the studies interact with IRBs [institutional review boards] about. The
IRB will ask questions like, “Don’t
we know this already?” How can you
randomize a patient with severe apnea
to CPAP versus placebo?
Quan: You have to ask whether
there’s equipoise. Certainly, you can
do it for 6 months or longer. In the
APPLES study1 we had a sham arm
of 6 months, and the amount of time
from when people were first identified for possible recruitment to when
they finished the study was probably
in excess of 8 months. Most of those
people have had the condition for a
long time. You could argue that every
second counts and you’ve got to get
them treated, but that’s not going to
answer your question.
1. Kushida CA, Nichols DA, Quan SF, Goodwin JL, White DP, Gottlieb DJ, et al. The
apnea positive pressure long-term efficacy
study (APPLES): rationale, design, methods, and procedures. J Clin Sleep Med 2006;
2(3):288-300.
Gay: I was thinking about that when
I saw you had an oxygen arm in that.
Are you worried that you might make
them worse with oxygen, by prolong-
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CARDIOVASCULAR DISORDERS
ing apneas in someone with severe apneas? Oxygen isn’t the standard of care
anywhere for OSA, so I’m curious how
you got to that oxygen arm.
Quan: The mortality data are in
PLoS Medicine.1 The cardiovascular
data2 are under revision, hopefully the
last revision.
Quan: The oxygen was put in there
because of our data from the Sleep
Heart Health Study1 that hypoxemia
appears to be factor responsible for
the increase in cardiovascular disease
with sleep apnea. Some data indicate
that oxygen might prolong the apneas.
However, there are some exclusions
from HeartBEAT for people with very
bad sleep apnea.2 I’ve also given oxygen in the clinic to people who have
refused to wear CPAP, and they did
not appear to get worse.
1. Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O’Connor GT, et
al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med
2009;6(8):e1000132.
2. Gottlieb DJ, Yenokyan G, Newman AB,
O’Connor GT, Punjabi NM, Quan SF, Redline S, et al. Prospective study of obstructive sleep apnea and incident coronary heart
disease and heart failure: the sleep heart
health study. Circulation 2010;122(4):352360.
1. Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O’Connor GT, et
al. Sleep-disordered breathing and mortality: a prospective cohort study. PLoS Med
2009;6(8):e1000132.
2. Redline S. Phase II trial of sleep apnea treatment to reduce cardiovascular morbidity.
http: // projectreporter.nih.gov / project_info_
description.cfm?aid⫽7853407. Accessed
June 24, 2010.
Gay: We all have.
Quan: So I don’t worry too much
about that, personally.
Mokhlesi: How do you translate
this? And I assume that some of the
data from the Sleep Heart Health Study
has not been published yet.
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Mokhlesi: I understand the importance of population-based studies,
but what do you do when you have
a woman who is 50 years old and
has severe OSA with an AHI of 50?
At the end of the day, we don’t treat
populations, we treat patients. How
do we connect these? Do you think
there’s a danger of people in the community interpreting these data and
saying that a 50-year-old woman
with an AHI of 50 shouldn’t even
get treated, because there’s no mortality benefit?
Quan: Even if sleep apnea wasn’t
a risk factor for any subsequent disease, if the person is symptomatic,
it’s reasonable to treat them. But
what about a person with an AHI of
50 but they’re asymptomatic? I don’t
think the data are conclusive enough
to say that I wouldn’t treat that individual. I might point out to the person that perhaps it’s a little unclear,
but I think that they might want to
give this a try.
Malhotra: I think that’s the most important point. In the Sleep Heart Health
Study there are very few women in
their 50s with AHIs in the 50s. I think
people are drawing conclusions that
aren’t supported by the data.
Quan: Absolutely.
Parthasarathy: Are there gender
differences in biomarkers?
Quan: I don’t know. I have no doubt
that there probably are differences, but
I haven’t completely reviewed that literature yet.
Malhotra: Which biomarkers?
Parthasarathy: Any.
Malhotra: We have done vascular
studies in a cohort of obese OSA patients and matched controls, and have
seen some gender differences.
Parthasarathy: You mean that the
augmentation makes a difference?
Malhotra: We have some data that
are not yet published.
RESPIRATORY CARE • OCTOBER 2010 VOL 55 NO 10